2-methyl-delta2-corticoids



United States Patent 3,341,524 Z-METHYL-A -CORTICOIDS Albert Bowers and James C. Orr, Mexico City, Mexico, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Sept. 15, 1961, Ser. No. 138,265 The portion of the term of the patent subsequent to Oct. 2, 1979, has been disclaimed 26 Claims. (Cl. 26t)239.55)

CHBOR C|3H2OR 6 0 0:0

L... OH NWR X: R

(IJHaOR i In the above formulas X represents B-hydroxy or keto; Y represents hydrogen, fluorine or chlorine; Z represents hydrogen, fluorine, chlorine or methyl; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R represents hydrogen, a-methyl, fi-methyl, a-hydroxy or tat-hydrocarbon carboxylic acyloxy of less than 12 carbon atoms; and R and R each represent hydrogen or the residue of a hydrocarbon radical containing up to 8 carbon atoms of straight, branched, cyclic or mixed aliphatic-cyclic chain, saturated or unsaturated and including aromatic groups.

The acyl groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy CHzOR containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propi-onate, enanthate, ben- Zoate, trimethylacetate, t-bntylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and ,e-chloropropionate.

The novel compounds of the present invention are prepared by the process illustrated by the following equation:

In the above formulas X, Y, Z and R have the same meaning previously set forth; A represents a double bond or a saturated linkage between C4 and 0-5.

In practicing the process just outlined the starting compound (I) which is 2-formyl-17,20; 20,2l-bismethylenedioXy-A -allopregnen or a 2-formyl-17,20; 20,21-bismethylenedioxy-A -pregnadien derivative (obtained in accordance with our copending US. patent application Ser. No. 138,267 filed of even date herewith) now Pat. No. 3,086,-

013 is treated with ethanedithiol in the presence of an acid such as a saturated solution of hydrogen chloride in acetic acid, alfording the corresponding dithioacetal, which upon reaction with Raney nickel in a suitable solvent, preferably acetone, at reflux temperature for a period of time of the order of 6 hours, furnishes the corresponding 2-methyl-17,20; 20,2l-bismethylenedioxy derivative (II). Hydrolysis of the 17,20; 20,21-bismethylenedioxy group in an acid medium such as formic acid furnishes the corresponding Z-methyl-l7a,2l-di-ol-20-one derivative (III).

The above obtained compounds with a primary hydroxyl group such as the Zl-hydroxyl and/ or a secondary hydroxyl such as the C16o-hydroXyl are conventionally acylated in pyridine with an acylating agent, as for example acetic anhydride or propionic anhydride, affording the corresponding monoor di-acylates.

The above mentioned compounds with a hydroxyl group at (3-160: and at C-l7ot are converted into the l7a-cyclic acetal or 16a,l7acyclic ketal by reaction with an aldehyde or ketone such as acetone, formaldehyde, paraldehyde, acetaldehyde, acetophenone, benzophenone, methyl ethyl ketone, diethyl ketone and other similar aldehydes and ketones in the presence of an acid catalyst such as perchloric acid or hydrochloric acid.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

Exampl l ness. Recrystallization from cycloethylene dithioacetal of ether-hexane afforded the the starting compound.

A solution of 4 g. of the above dithioacetal dissolved in 3 1t. of acetone was boiled under relux for 6 hours with 50 g. of Raney nickel. The metal was removed by filtration and washed well with hot acetone. The filtrate was evaporated to dryness, dissolved in chloroform and washed with dilute hydrochloric acid, sodium carbonate solution and Water. Drying, evaporation and crystallization of the residue from acetone-hexane furnished 2,160:- dimethyl 60c fluoro-17,20; 20,2l-bismethylenedioxy-A allopregnen-l l-one.

The following starting compounds were treated by the above procedure, giving the products hereinafter set forth:

Starting Compound Product Product 2,16fl-dimethyl-6a,9a-difluoro- 17,20; 20,2l-bismethylcnedioxy- A -preguadicn-ll-one.

2,GaJGfl-trimethyl-17,20; 20,21-

bismethylencdioxy-N -pregnadien-ll-onc.

chlro-l7,20; 20,21-bisrnethylencdioxy-A -pregnadien-ll-one.

lfia-ol-ll-one. nadien-lfia-ol-lbone. 2-forrnyl-l7,20; 20,2l-bismothylene- 2-methyl-17,20; 20,21-bismethyl- 1 5 dioxy-A -prcgnadicn-llfl-ol. encdioxy-NA-pregradien-l16-01.

Example 11 20 1 g. of 2.160: drmethyl 6a fluoro 17,20; 20,21-b1smethylenedwXy-A -allopregnen-1l-one was heated on the steam bath with 100 cc. of 80% acetic acid under nitrogen for 7 hours, 1t was then concentrated under vacuum to a small volume and poured into Water. The precipitate was collected, washed Well with water, dried and recrys tallized from acetone-hexane, thus furnishing 2,16a-d1 methyl-6a-fiuoro-A -allopregnen-17a,2 l-drol-l l,20-dione.

By the sam eprocedure there were treated the starting compounds listed below affording the corresponding products hereinafter set forth.

Starting Compound Product 2,l6r1-dimothyl-6a,9a-(lifiuoro'l7, 2,l6a-dimethyl-6a,9a-difluoro- 20;20,2l-bismethylencdioxy- A -alloprcgnen-1711,21-di0l-11,

A -allopregnen-ll-one. 20-di0nc.

2,16a-dimcthyl-fia-fluoro-tlu-chloro- 2,1(la-dimcthyl-Ga-HuOrO-Qa- 17,20; 20,21-bismcthylenedioxychloro-A -alloprcgnen-17 (1,21- A -allopregnen-ll-one. diol-11,20-dione.

2,16a-dimcthyl-6a-fluoro-17,20; 20, 2,16a-dimethyl-fia-fluoro-A allo- 21-bismcthylenedioxy-A -allopregnen-l1/3,17a,21-triol-20-one.

20;20,2l-bismethyleuedioxy- A -allopregnen-l7a,2l-diol-11,

A -alloprogncn-ll-one. 20 di0ne.

2,611,lfifl-trimethyll7,20; 20,21- 2,6a,lfi/i-trimcthyl-A -allopregnenbismethylenedioxy-N-allopregl7ct,21-diol-l1,20-dione. ncn-ll-onc.

2,6a,16fi-trimethyl-17,20; 20,21- 2,6a,16,8-trirnethyl-N-alloprcgncnbismcthylenedioxy-A -alloprcg- 1lB,17a,21-triol-20-one. nondlfl-ol.

2rnethyl-9a.-fiuoro-l7,20; 20,21- Z-methyl-0a-fiuoro-A -allopregnenbismethylencdioxy-N-allopreg- 116,16a,l7a,21-tetrol-20-one. non-115,16a-diol.

0 2-rnethyl-17,20; 20,21-bismethylcne- 2-mcthyl-N-allopregnen-ll/SJ7a,

dioxy -alloprcgnondlfl-ol. 21-triol-20-onc.

2,6a-dimethyl-l1,20; 20,21- 2,(ia-dimethyl-N-allopregnenbismcthylonedioxy-A 11 5,16a,17a,2l-tetrol-20-one. allopregnen-11B,l6o.-diol.

pregnadien-llfl-ol. one.

bismethylenedioxy-A 116,1711,21-131101-20-0110.

pregnadiemllfi ol.

pregnadie11-l15,16a,17 11,21-t0t1'0l- 20-one.

Starting Compound Product 2-m ethyl-A pregnadien-11B,17a,

21-triol-20-one.

2,6.1-dimethyl-A -pregnadien-llfi,

1611,17 a,2l-tetrl-20-one.

Example 111 A mixture of 1 g. of 2,16e-dimethyl-6a-fiuoro-A al1opregnen-17a,2l-diol-l1,20-dione, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overngiht, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave the 21 acetate of 2,16a-dimethyl-6u-fluoro-A -allopregnen-17a,21-diol-11,20-dione.

Following the above technique were treated the starting compounds hereinafter listed, furnishing the products indicated below:

Starting Compound Product 2-methyl-n allopregnen-llfl,17a,21-

triol-wone.

2,6a-dimethyl-A 'allopregnen- 115,160.,1711,21-1ZGUOI 20-0118.

Starting Compound 2,611,l6B-trimethyI-A -pregnadien- 11 9,1711, 2l-triol-20-0ne.

2-methyl-A -pregnadiendlfidh,

21-triol-20-one.

2,6a-dimethyl-A -pregnadien-11,B,

16a,17e,21-tetrol-20-011e.

Product tetrol-20-one.

Following the above described procedure, but substituting acetic anhydride by propionic anhydride, caproic anhydride, cyclopentylpropionic anhydride and benzoyl chloride, there were correspondingly obtained the propionates, ca-proates, cyclopentylpropionates. and benzoates of the hereinabove listed starting compounds.

Example IV To 120 cc. of acetone containing 1 g. of 2-methyl-6achloro-9a-fluoro-A -allopregnene-16a,17a,2l triol 11,20- dione, prepared in Example II, were added 30 drops of 78% perchloric acid. After one hour at room temperature, 30 drops of pyridine were added and the resulting solution was evaported to dryness under reduced pressure. 30 cc. of Water were then added to the residue and it was then extracted several times with 80 cc. of ethyl acetate. The combined extracts were washed to neutrality with water, dried over sodium sulfate and evaporated to dryness. The residue upon trituration with methanol gave a crude 16,17-acetonide, Recrystallizations from the same solvent afforded the 16,17-acetonide of 2-methyl-6mchloro-9ot-fluoro-A -allopregnene-16a,17 x,21 triol 11,20- dione.

By following the same procedures, there were treated the starting products listed below and there were obtained the corresponding 16,17-acetonide products hereinafter listed:

Starting Compound Final Product Z-methyl-Qa-fluoro-A -pregnadiene-16a,17a,21-triol-11,20-di0ne.

2,6a-dimeth yl-A -pregnadiene- 11 3,16e,17a,21-tetr01-20-one.

Example V By following the procedure described in Example IV except that acetone was substituted by benzaldehyde, paraformaldehyde and cyclohexanone, there were obtained respectively the corresponding 16a,l7a-benzylidenedioxy, 16oz, l7u-methylenedioxy and 16oz,17oc-CyCl0hBXanOne ketal derivatives of the starting compounds of Example IV.

Example VI The final products described in Examples 1V and V were transformed into the corresponding 21-acetates, 21-propionates, 21-caproates, 21-cyclopentylpropionates and 21- benzoates in accordance with the methods described in Example 111.

We claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is a member of the group consisting of hydrogen, lit-methyl, fl-methyl, a-hydroxyl and an &- acyloxy group derived from a hydrocarbon carboxylic acid of less than 12 carbon atoms; X is selected from the group consisting of fi-hydroxyl and keto; Y is a member of the group consisting of hydrogen, fluorine and chlorine and Z is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

2. 2,16wdimethyl 60a fluoro-A -allopregnen-17a,21- diol-11,20-dione.

3. 2,16a-dirnethyl 6oz fluoro-9a-chloro-A -allopregnen-17 u,21-diol-11,20-dione.

4. 2,16a-dimethyl 604,9 difluoro-A -allopregnen- 17a,21-diol-11,20-dione.

6. 2,16a-dimethyl 6a 21-triol-20-one.

7. 2,16fl-dimethyl 611,9wdifluoro-A -allopregnen-11B, 176,21-trio1-20-one.

8. 2,16f3-dirnethyl 6a,9a-difiuoro-A -allopregnen-17a, 21-diol-11,20-dione.

9. 2,6u,16fl-trimethyl A allopregnen-17a,2l-diol-l1, 20-dione.

10. 2,6a,16B-trimethyl A allopregnen11fl,17u,21 triol-20-one.

11. 2-methyl-6a-chloro-9a-fiuoro A -allopregnen-16a, 17a,21-triol-11,20-dione.

12. 2-methyl-6u-chloro-9a-fluoro A -allopregnen-11,6, 16d,17a,21-tetrol-20-one.

604,9 difiuoro-M-allopregnenfluoro-M-allopregnen-l 1,8, 17 0c,

13. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is a member of the group consisting of hydrogen, u-methyl, fi-methyl, a-hydroxyl and an acacyloxy group derived from a hydrocarbon carboxylic acid of less than 12 carbon atoms; X is selected from the group consisting of ,B-hydroxyl and keto; Y is a member of the group consisting of hydrogen, fluorine and chlorine and Z is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.

14. 2,16a-dimethyl-6a-fluoro A -pregnadien-17a,21- dio1-11,2()-dione.

15. 2,16a-dimethyl-6a-fluoro-9or-chloro A -pregnadien-17u,21-diol-11,20-dione.

16. 2,16u-dimethyl-6a,9a-difluoro A pregnadien- 17a,21-diol-11,20-di0ne.

17. 2,16u-dimethyl-6a,9o A pregnadien-11fi,17a, 21-triol-20-one.

18. 2,16a-dimethyl-6u-fluoro-9u-chloro A -pregnadien-l 1B, 17a,21-t110l-20-0116.

19. 2,16,6-dirnethyl-6a,9a-difiuoro A pregnadien- 11fi,17a-triol-20-one.

20. 2,16fi-dimethyl-6a,9u-difluoro A pregnadien- 17a,21-di0l-11,20-di0ne.

21. 2,6oc,16,B-trimethyI-A -pregnadien 1704,21-di0l-11, 20-dione.

22. 2,6a,16[3-trimethyl A pregnadien-11fl,17a,21- triol-20-one.

23. Z-methyl-6a-chloro-9a-fiuoro A pregnadien- 16oc,l7ot,21-tfiOl-l1,20-(110116.

24. Z-InethYl-Got-ChlOIO-9ot-fl1l0f0 A pregnadien- 11;3,16a,17a,21-tetrol-20-one.

25. A compound of the following formula:

26. A compound of the following formula:

(IJHZOR wherein X is selected from the group consisting of 5- hydroxyl and keto; Y is a member of the group consisting of hydrogen, fluorine and chlorine; Z is selected from the group consisting of hydrogen, fluorine, chlorine and methyl; is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R and R are each selected from the group consisting of hydrogen and a hydrocarbon radical containing up to 8 carbon atoms.

References Cited OTHER REFERENCES 15 Fieser et al., Steroids, pp. 692-696 (1959), Reinhold Pub. Co., New York, NY.

LEWIS GOTTS, Primary Examiner. MORRIS LIEBERMAN, Examiner.

G. E. LANDE, H. FRENCH, E. L. ORBERTS,

Assistant Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,341,524 September 12, 1967 Albert Bowers et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 8, line 34, for "6ot,9a-A read 60.,90 difluoro-a column 9, lines 19 and 20, for "methyl is" read methyl; R is Signed and sealed this 21st day of January 1969.

(SEAL) Attest:

Edward M. Fletcher, Jr. EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

25. A COMPOUND OF THE FOLLOWING FORMULA: 